For an overall view of the field of the art to which the invention pertains, reference may be made for instance to Moës A. J., “Gastroretentive Dosage Forms”, Critical Reviews in Therapeutic Drug Carrier Systems 10(2):143-195 (1993), and also to Singh B. N. et al., “Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention”, Journal of Controlled Release 63(3):35-259 (2000).
Pharmaceutical tablet systems capable of prolonged floating in or on gastric fluid e.g. so as to have a long time of residence in a patient's stomach for releasing therein a pharmaceutically active substance in sustained manner are known in the art. Generally, pharmaceutical forms having a long time of residence in a patient's stomach are of great interest, not only because they allow a local treatment of the patient's stomach wall and more particularly of the gastric mucous membrane, but also and above all because they allow to release active substance in the vicinity of the patient's duodenum, which is a very favourable location of the gastro-intestinal tract where a great many active substances are best absorbed.
There are several approaches for bringing about a prolonged time of residence in the stomach.
A tablet system can be formulated so as to adhere to the gastric mucous membrane (cf. for instance U.S. Pat. No. 5,213,794, U.S. Pat. No. 5,571,533, WO-A-93/24124, WO-A-98/42311, WO-A-98/52547). A major drawback of such adhering systems resides in the difficulty of bringing about that they reliably adhere and remain adherent to the gastric mucous membrane, for the latter is continually undergoing changes and replacement processes and is also subject to the peristalsis i.e. to strong contractions that take place at the stomach wall. In respect of adherence to the gastric mucous membrane no helpful knowledge can be derived from currently used pharmaceutical forms designed to adhere e.g. onto nasal or buccal surfaces, because such forms need to be pressed onto said surfaces at application time, which pressing is not possible onto a patient's gastric mucous membrane, to say nothing of the hazard of the forms getting stuck in the patient's esophagus.
A tablet system can also be formulated to have a high apparent density that, following ingestion, will cause the system to settle in the stomach at the lower portion of the antrum (cf. for instance U.S. Pat. Nos. 4,193,985, 5,374,430). However, the movement of substances contained in the stomach towards the lower portion of the antrum participates in the natural sequence of events related to gastric discharge and hence, pharmaceutical forms formulated so as to settle in the antrum are likely to pass the patient's pylorus either with the bolus (during the digestion process) or together with undigested debris (in the time interval between two successive digestion processes). Thus, to secure the gastroretention of systems formulated so as to have a high apparent density, such systems must additionally be given some properties that will promote the gastroretention, which will raise again the problems already discussed above. Indeed, in EP-A-526862 a granulate is disclosed that not only has a high density but also is given muco-adhesive properties.
A tablet system can also be formulated so as to grow in the stomach, following ingestion, to a size large enough to hinder the system from passing the patient's pylorus even when the latter is open. A great many of these systems are either folded at ingestion time and made to unfold and open out in the stomach following ingestion (cf. for instance EP-A-202159, U.S. Pat. Nos. 4,735,804, 4,758,436, 4,767,627, 5,002,772) or they are made to swell in the stomach following ingestion, for example as a result of gelling (cf. for instance U.S. Pat. Nos. 4,434,153, 5,651,985) or carbon dioxide emission (cf. for instance U.S. Pat. No. 4,996,058, WO-A-98/31341). However, systems formulated to swell could easily pass the patient's pylorus during the latency period that runs from ingestion time until the system has grown to a sufficient size for the gastroretention mechanism to become effective. On the other hand, systems formulated to unfold and open out in the stomach might well be retained permanently in the stomach or even in the esophagus, due to early activation of the deployment mechanism. Each of such failure cases will cause severe secondary effects.
A tablet system can also be formulated with agents that delay or slow down the transit through the stomach, such as lipid-based vehicles (for instance, fatty acids) or depressors of the central nervous system (for instance, serotonine antagonists). These agents bring about a reduction of the stomach motility, which in turn slows down the gastric discharge. Such a way of bringing about gastroretention is most often used in association with other ways (cf. for instance WO-A-97/47285). However, as systems that bring about a reduction of the stomach motility interfere with the whole mechanism of gastric discharge, they are likely to cause digestion problems or worsen them, if already existing. Furthermore, the use of a serotonine antagonist has to comply with pertaining health and drug regulations.
Hence, all known tablet systems of the above mentioned types must be deemed unreliable in respect of providing a prolonged time of residence in the stomach and therefore, they all are unsuitable for providing reliably an alternate succession of periods of substance release and no-release with at least two periods of substance release separated by one period of no-release e.g. when structured in accordance with the teaching of EP-A-788790.
A tablet system can also be formulated to float on the content of the stomach.
The buoyancy of such a tablet system may be provided by means of an initially dense matrix that undergoes gelling in the stomach following ingestion, which causes the matrix to swell and hence, reduces its density (cf. for instance GB-A-1546448, U.S. Pat. Nos. 4,126,672, 4,140,755, 4,167,558, 5,169,639, 5,360,793, WO-A-96/29054); or the buoyancy of such a tablet system may be provided by means of a film or coating that undergoes carbon dioxide emission in the stomach following ingestion, which causes the film or coating to foam (an effect that may be understood as a special type of swelling) and hence, reduces its density (cf. for instance U.S. Pat. Nos. 4,101,650, 4,844,905, WO-A-98/47506); or the buoyancy of such a tablet system may be obtained by providing it right from the start (i.e. before ingestion) with a density that is sufficiently low to keep the tablet system floating in the stomach following ingestion (cf. for instance JP-A-3-101615, U.S. Pat. Nos. 3,976,764, 4,702,918, 4,814,178, 4,814,179, 5,198,229, 5,232,704, 5,288,506, 5,626,876).
Besides the fact that some of these tablet systems formulated to float on the content of the stomach may have their own severe drawbacks, all these systems (with the single exception of the above-mentioned U.S. Pat. No. 4,140,755) only bring about a single period of release of active substance (irrespective of the fact that the active substance may actually consist of a mixture of active compounds). As to the system disclosed in the above-mentioned U.S. Pat. No. 4,140,755, this latter system can only bring about a single immediate release of active substance followed by a single prolonged release of the same active substance.
Thus, none of the above-mentioned tablet systems formulated to float on the content of the stomach is capable of providing reliably a “multipulse release” consisting of an alternate succession of periods of substance release and no-release, which alternate succession would include at least two periods of substance release separated by one period of no-release.
Yet, such a multipulse release capability is highly desirable in a tablet system formulated to float on the content of the stomach, for it would allow a patient to take one single drug unit form to produce a drug plasma level scheme that can only result at present times from administering to the patient two or more standard-type fast-release drug unit forms to be taken in succession at respective predefined time instants separated by respective predefined latency or waiting periods.
Pharmaceutical tablet systems having a multipulse release capability are known in the art.
One type of a pharmaceutical tablet system having a multipulse release capability is known for instance from EP-A-1074249 and is constructed as a multilayered body arranged concentric about a core, which core is fully enclosed within layers that fully enclose one another in succession. The core is the last part of the tablet system that will disappear by dissolution or digestion in gastric fluid or by gastric discharge and hence, to confer prolonged buoyancy to such a tablet system and prevent any early sinking or discharge thereof, at least the core should be formed of lightweight materials. Moreover, in consideration of the possible gastric discharge of the core, a reliable administration can only be attained with a core devoid of any active substance that participates in the desired multipulse release capability, which is not an economical construction because of the necessarily large size of the core.
Another type of a pharmaceutical tablet system having a multipulse release capability is known for instance from WO-A-91/04015, EP-A-631775 or EP-A-788790 and is, basically, made up of planar layers superposed in a stack that is enclosed within an envelope so as to leave at least one outer face of an outer layer of the stack uncovered and unprotected by the envelope. In particular, there is disclosed in EP-A-788790 a pharmaceutical tablet system to be administered by the oral route for releasing one or more pharmaceutically active substances in the course of an alternate succession of periods of substance release and no-release, said alternate succession including at least two periods of substance release separated by one period of no-release. This type of pharmaceutical tablet system is neither intended nor provided for prolonged floating in or on gastric fluid in a patient's stomach.
To nevertheless confer buoyancy to this type of pharmaceutical tablet system, it may be envisaged to use lightweight materials to form the envelope, and this may be expected to be easiest in a tablet system having a cup-shaped envelope and a multilayered core placed therein, as disclosed in EP-A-788790. The cup-shaped envelope is the last part of the tablet system that will disappear by dissolution or digestion in gastric fluid or by gastric discharge and hence, to confer prolonged buoyancy to such a tablet system and prevent any early sinking or discharge thereof, at least the cup-shaped envelope should be formed of lightweight materials. Moreover, in consideration of the possible gastric discharge of the cup-shaped envelope, a reliable multipulse release can only be attained with a cup-shaped envelope devoid of any active substance that participates in the desired multipulse release capability.
Lightweight materials, the use of which may be envisaged in pharmaceutical tablet systems of the above-mentioned type having a multipulse release capability, are known e.g. from the prior art mentioned above. Also, fatty and/or waxy lightweight materials have been used to obtain tablet systems having a low density, for instance according to JP-A-1-016715 that discloses a system having a fatty core made up of fats and oils of density —0.98 and at least one coating layer that contains active substance.
However, these known lightweight materials will not withstand a prolonged floating in or on gastric fluid, as some will dissolve in the gastric fluid, which will cause a progressive loss of buoyancy and subsequent gastric discharge of the tablet system, and others will experience a change of volume e.g. due to gelling that in turn will entail changes of shape allowing the core to eventually become detached from the cup-shaped envelope: in either case the multipulse release characteristics will be unreliable. In a pharmaceutical tablet system of the type mentioned above made up of a stack of superposed layers that is enclosed within an envelope with an outer layer of the stack having an outer face left uncovered and unprotected by the envelope, any poor contact and attachment between the stack of layers and the envelope will allow gastric fluid to infiltrate the system, causing fragility of the tablet system as well as undesirable variations more particularly of the in vivo release rate of the active substance from the innermost i.e. lowermost layer of the stack, producing the so-called “dose dumping”. In the particular tablet system having a cup-shaped envelope and a multilayered core placed therein (as disclosed in EP-A-788790) the caused fragility of the tablet system may even allow the core to detach from the cup-shaped envelope.
Also, fats and oils that are currently used (alone or in mixture) in pharmaceutical tablet systems to confer them a density that is lower than unity do not allow tablet production using a compression step of the kind performed in any currently used type of tablet compression apparatus, because of feeding and sticking problems: such fats and oils (whether taken as powders or liquids) have flow properties that do not allow to reliably and evenly fill the press moulds, and during the compression step they stick to the moulding plug and die, impairing the compression efficiency and uniformity.